Summary of Work: The primary focus of the Secondary Prevention Project involves the observation that early intervention with antipsychotic medications for schizophrenic patients decreases the long-term morbidity of the illness. If antipsychotic medications do influence long-term morbidity, then a mechanism of how they do this can be proposed. Repeated exacerbation of most medical disorders (such as ischemia or inflammation) leaves scars. The early intervention studies explore how psychosis and early intervention might affect the course of schizophrenia, and how our understanding of that mechanism might lead to better treatments for patients. Foremost among these studies is the National Collaborative Study of Early Psychosis and Suicide (NCSEPS), which is being conducted in conjunction with the Department of Defense (DOD) and the Department of Veterans Affairs (VA).In addition to NIMH, DOD, and VA staff, the NCSEPS Executive Advisory Board participates in the NCSEPS project. Board members have diverse research and professional interests. They participate in conference calls monthly and meet twice a year to propose new research avenues and discuss project results. The goals of this project are to develop methods to detect and decrease the occurrence of long-term morbidity associated with major psychiatric disorders, particularly bipolar disorder, major depressive disorder, and schizophrenia; to decrease the risk of suicide; to determine what benefits result from early intervention in patients first manifesting signs of these illnesses; and to assess the characteristics of this first-episode population. During the last few years, increasing evidence has suggested that early intervention in schizophrenia improves its long-term outcome. Because of some similarities with bipolar illness, there is reason to believe that early intervention in that illness might also decrease long-term morbidity. Also, because both illnesses are associated with a high risk of suicide, particularly early in their course, it is possible that early intervention might attenuate that risk as well. The Armed Forces provide an excellent opportunity to study the potential benefits of early intervention in the major psychoses. Historically, a number of articles published over the course of this century indicate that a high percentage of individuals who become psychotic while in the military do so early in the course of their military career. This is particularly intriguing because it suggests that the onset of psychosis is highest during periods that demand the greatest social adaptation, with its accompanying psychological and emotional stress. For active duty Armed Forces personnel who are not directly involved in front-line military conflicts, the earliest period of service (eg, basic training) is likely to require the greatest level of social adaptation. Furthermore, there are a number of potential advantages to carrying out such a project within the DOD. For instance, the highest risk period for developing schizophrenia and bipolar disorder occurs in the age range when most individuals enter the Armed Forces; the relatively controlled environment individuals are subjected to in the Armed Forces provides an almost unique opportunity to provide help; and studying servicemen and servicewomen provides the potential to follow-up those individuals who develop an illness through the VA. To date, NCSEPS has amassed sociodemographic characteristics and hospitalization records for over 10,000 patients and over 50,000 controls. Patients were active duty military personnel who had their first hospitalization for a major psychiatric disorder between 1991 and 1998. Furthermore, individuals first diagnosed in the DOD are followed into the VA system. The earliest data collected by the NCSEPS project focus on determining who is most vulnerable to these disorders, and how current methods of caring for them might be strengthened. Although analyses of these data are ongoing, a number of interesting preliminary findings have emerged. ospitalizations within the first 15 days. The percentage of patients hospitalized within the first year of active duty who were also hospitalized within the first 15 days was 40.1% of those with bipolar disorder, 14.3% percent of those with major depressive disorder, and 37.3% percent of individuals with schizophrenia. All three patient groups had a high risk of hospitalization during the first 15 days of active duty, although the risk was much greater for bipolar disorder and schizophrenia than for major depressive disorder. Compared with males, females had an elevated relative risk of being hospitalized for bipolar illness and major depressive disorder, but not for schizophrenia, during the first 15 days of active duty. Substance abuse in NCSEPS patients. Almost 25% of patients hospitalized in the DOD with bipolar disorder, major depressive disorder, and schizophrenia between 1992 and 1996 had a comorbid diagnosis of alcohol (20%) or drug abuse (2%), or both (2.5%). Rates of comorbid diagnosing rose slightly but steadily between 1992 and 1996. Interestingly, Cannabis Dependence and Abuse comprised between 40 and 50% of all the drug abuse in the DOD sample. No significant differences were found among diagnostic groups. Of the patients seen in the VA with a diagnosis of bipolar disorder, major depressive disorder, or schizophrenia, 32% also had a comorbid diagnosis of substance abuse in the VA (an increase of about 7%). Of this subgroup, about 55% were new cases of substance abuse, meaning that they had not had a comorbid diagnosis in the DOD. Use of VA services by NCSEPS sample. Of those active duty patients hospitalized in the DOD with bipolar disorder, major depressive disorder, or schizophrenia between 1992 and 1996 who were eligible to receive follow-up care through the VA, 58% received medical treatment as either inpatients or outpatients, and an additional 1.7% were receiving VA disability compensation, but no mental health care; thus, approximately 60% were receiving some benefits or treatment from the VA. A greater percentage of the patients diagnosed with schizophrenia in the DOD receive inpatient or outpatient treatment in the VA than those diagnosed with bipolar disorder who, in turn, are seen more frequently than those initially diagnosed with major depressive disorder in the DOD. Roughly half (47% to 60%) of those who sought treatment were first seen in the VA 60 or more days after their date of separation from the DOD. Based on what we are learning about both patients who become ill and the DOD and VA healthcare systems, interventions will be designed. The most likely intervention is one that ensures care is provided after an individual is discharged from the DOD and becomes eligible for care in the VA system; presently, not all DOD patients who are eligible seek followup are through the VA. Using methods designed for a previous study of homeless men in New York City, we hope that a time-limited bridge between the DOD and VA can prevent future relapses. The NCSEPS project is particularly important because of its ability to follow a large number of patients before the onset of their illness through the VA system, and because of the availability of substantial amounts of pre- and post-morbid data. Future studies should be able to determine how a number of biological and psychological changes correlate with the course of the illness, and whether some of the adverse consequences of these illnesses are preventable.* Medication discontinuation and relapse in patients with schizophrenia A number of issues have recently arisen related to the safety of medication-free periods. For instance, concerns have arisen about the course of illness in patients who choose to leave organized medication-free periods early, before they have a chance to be placed back on antipsychotic medications. Related to this is the issue of how long it takes patients with schizophrenia to recover to baseline functioning after antipsychotic medications have been reinstituted. Furthermore, there are questions concerning whether repeated medication-free periods, in this population of patients, lead to an increasingly poor response to treatment. It has been hypothesized that placebo periods may increase long-term morbidity for patients with schizophrenia. In this study, medication discontinuation was studied in a group of over 100 patients with chronic schizophrenia who were placed on an experimental protocol involving a placebo period of at least seven days at the NIMH Neuropsychiatric Research Hospital between 1982 and 1994. It was found that, by discharge, patients? rating scores on the Psychiatric Symptom Assessment Scale (PSAS) (a BPRS-like rating scale) had returned to baseline. Scores for a comparison group of patients hospitalized during the same time period and under the same conditions, but who did not undergo a placebo period were also assessed.Scores for patients in the comparison group had also not altered between baseline and discharge. When the six-week response of placebo patients to the reinstitution of antipsychotic medications was studied, it was found that, the speed with which patients recovered was highly variable. As a group, the patients had not returned to baseline 6 weeks after medications were restored. Individually, however, 25% of the patients had recovered to baseline, and 53% had recovered to their baseline mean plus one standard deviation by day 3 after medications were restored. Similarly, 50% of the patients had recovered to baseline, and 66% had recovered to their baseline mean plus one standard deviation by day 42 of the post-placebo phase.Again, by discharge patients were doing as well as they had at baseline. All patients who left the placebo study early received at least three days of antipsychotic medications before leaving the hospital. These patients appeared to improve at the same rate as the patients who had at least six weeks of antipsychotic medications. There is no indication that these patients responded more poorly to treatment than those who received at least six weeks of medication. The results indicate that given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline, but that the speed with which they attain that recovery is highly variable.